Baseline socioeconomic status predicting post-COVID-19 symptoms: Results from Isfahan COVID Cohort (ICC) study

Highlights • Low socioeconomic status (SES) increased the risk of long COVID-19 cardiovascular symptoms in the whole population.• Hospitalized patients with low SES had a higher risk of long COVID-19 cardiovascular symptoms.• Non-hospitalized patients with low SES had a lower risk of long COVID-19 cardiovascular symptoms.• SES was not associated with long COVID-19 general and respiratory symptoms.


Introduction
The Centers for Disease Control and Prevention (CDC) have introduced the term "Post-Acute Sequelae of COVID-19″ or post-COVID to describe symptoms associated to COVID-19 that persist beyond four weeks (Centers for Disease Control and Prevention, 2021).These persistent symptoms commonly include fatigue, dyspnea, depression, insomnia, anxiety, and memory loss (Han et al., 2022).The prevalence of persistent symptoms is reported as high as 87 % and 50 % among hospitalized and non-hospitalized patients, respectively (Carfì et al., 2020;Armange et al., 2021;Xie et al., 2021).
The persistence of COVID-19 symptoms beyond the acute phase increases healthcare utilization and financial burden for both patients and the healthcare system (González-Hermosillo et al., 2021).Patients with low socioeconomic status (SES) may not seek advanced care due to increased costs and lack of health insurance.Additionally, individuals from lower SES circumstances who have experienced a lifetime of adversity are at an increased risk of having one or more health conditions (Berger et al., 2021), making them a high-risk population for adverse outcomes caused by COVID-19 (Langenberg et al., 2006).Previous studies have shown the association between lower SES and increased vulnerability, hospital admission, morbidity, and worsening outcomes of COVID-19 (Clouston et al., 2021;de Lusignan et al., 2020;Bambra et al., 2020;Holuka et al., 2020), though a number of studies reported higher rates of COVID-19 infection and mortality in highincome areas (Abedi et al., 2021;Khanijahani and Tomassoni, 2021).
Nevertheless, there is a limited literature presenting the relationship between SES and post-COVID symptoms.The main objective of this study was to determine whether SES is associated with post-COVID-19 symptoms among a population of hospitalized and non-hospitalized patients with COVID-19,

Study design and population
The Isfahan COVID Cohort (ICC) study is a 5-year longitudinal cohort study started in 2020.The design and methodology of the study were previously described in greater details (Sarrafzadegan et al., 2022).In brief, ICC aimed to evaluate the short-term and persistence comorbidities, their potential risk factors, and mortality rate of patients with COVID-19.ICC included patients who were hospitalized with moderate and severe symptoms of COVID-19 (World Health Organization, 2020).In addition, we recruited patients who were registered in health centers because of experiencing any mild symptoms of COVID-19 or exposing to someone with COVID-19 and were asymptomatic despite having a positive test result of RT-PCR for coronavirus.Therefore, the registered hospitalized and non-hospitalized patients with COVID-19 were invited to health centers located in the urban and rural areas in Isfahan.Hospitalized patients before March 10, 2020, and patients who did not have an RT-PCR test for COVID-19 or those with negative test result of RT-PCR were excluded.This study included 3912 patients who were followed-up for one year.The protocol of the study was approved by the ethics committee of Isfahan University of Medical Sciences (IUMS) (No: IR.MUI.MED.REC.1399.223).All the participants provided their informed consent in writing.

Data collection
Various aspects of general characteristics, such as age, sex and smoking status were determined.Moreover, information in terms of preexisting conditions including coronary heart disease, hypertension, chronic respiratory disease, diabetes mellitus (DM), cancers, and chronic kidney disease (CKD), as well as the medications and risk factors associated with these non-communicable diseases by interviewing patients at health centers using standardized questionnaire.Psychological factors were evaluated using validated Persian version of hospital anxiety and depression scale (Montazeri et al., 2003) and perceived stress scale (Nouri et al., 2018).Additionally, general physical examinations were conducted by GPs at health centers and recorded.Height and weight were measured while participants wore light clothes and no shoes to the nearest 0.5 cm and 0.5 kg, respectively.Body mass index (BMI) was calculated by dividing the weight in kilograms by the square of the height in meters.The measurement of waist circumference (WC) was done by placing the tape at the midpoint between the lower edge of the last rib and the top of the hip bone.On the other hand, the hip circumference was measured at the widest part of the buttocks using a non-elastic tape, with precision to the nearest 0.1 cm.The resting blood pressure was measured two times while participants were seated after 5 min of rest using an OMRON barometer.The average of the two measurements was taken for analysis.The definition of hypertension was based on having a mean systolic blood pressure ≥ 140 mmHg and/or mean diastolic blood pressure ≥ 90 mmHg, or taking antihypertensive medications (Williams et al., 2018).

Follow-up
Patients were contacted every six months and subsequently followed up for one year.If patients developed any new sign or symptom after discharging from hospital, they were referred by general physicians to the COVID-19 clinic and were visited by and internal medicine specialist.General physicians taught and asked all patients to attend this clinic if they developed any problem during the follow-up.

Primary endpoints
Post-COVID-19 was defined as the persistence of the symptoms or development of new symptoms for at least three months after COVID-19 onset.According to organ system involvement, self-reported post-COVID-19 symptoms were categorized into general (abnormal weight loss or gain, generalized fatigue, and loss of appetite), cardiovascular (chest pain, palpitation, lower extremity edema, cold extremities, paresthesia, color change in extremities, and early fatigue with physical activity), and respiratory (continuous and annoying cough, dyspnea, need for oxygen therapy, and wheezing) symptoms.

SES measurement
We evaluated the SES of participants using standard questionnaires including multiple-choice questions (Roohafza et al., 2021).Our online questionnaire has been filled out by the health centers' trained personnel.These questionnaires encompassed several indicators, including educational level, occupation, house room number, the number of trips taken, and using notebooks, laptop, or tablet in the house.The level of education was classified as low (≤5 years), medium (González-Hermosillo et al., 2021;Berger et al., 2021;Langenberg et al., 2006;Clouston et al., 2021;de Lusignan et al., 2020;Bambra et al., 2020;Holuka et al., 2020), and high (≥13 years).Occupation status was divided into governmental employed, self-employed, housewife, retired, unemployed, and student.We used latent class analysis (LCA) to summarize all the variables into one main total SES, and then was divided into two levels, less than median SES as "low SES" and higher than median SES as "high SES."

Statistical analysis
The baseline characteristics of subgroups were compared via Student's t test and chi-square test.The association between baseline SES with post-COVID-19 symptoms were examined using Cox proportional hazard analysis in separate steps.First, a crude model was performed with no adjustment for potential confounders.In additional analysis, model 1 adjusted for age (year), sex (male/ female), marital status (single/ married/ divorced or widow), region of residency (urban/ rural) and education.Model 2 additionally adjusted for comorbidities including DM, coronary heart disease, CKD, chronic respiratory disease, and cancer, smoking and hypertension (yes/ no).Model 3 additionally adjusted for severity of COVID 19 (hospitalized/ non hospitalized).P < 0.05 was considered statistically significant.All analysis were performed using SPSS version 24.

Results
A total of 3912 hospitalized and non-hospitalized patients with confirmed SARS-CoV-2 were included in this study, 1798 (45.9 %) of whom were female, and 2598 participants (66.4 %) reported post-COVID-19 symptoms.
The prevalence of reported post-COVID-19 symptoms based on SES level and hospitalization status is represented in Table 2.In hospitalized patients, there was a significant difference between low and high SES participants in terms of generalized fatigue (P = 0.041), loss of appetite (P = 0.002), wheezing (P = 0.008), and total respiratory symptoms (P = 0.044).Moreover, a significant difference was observed in total cardiovascular symptoms, lower extremity edema, cold extremities, paresthesia, and color change in extremities between the low and high SES groups in both hospitalized and non-hospitalized participants.
Post-COVID-19 symptoms were evaluated in relation to SES separately in hospitalized and non-hospitalized patients (Table 4).After full potential adjustment, there was a positive association (HR = 1.96; 95 % CI: 1.23-3.12;P = 0.004) and negative association (HR = 0.82; 95 %CI: 0.70-0.97;P = 0.017) between low SES and long cardiovascular COVID-19 symptoms in hospitalized and non-hospitalized patients, respectively.The general and respiratory symptoms did not show significant differences between low SES and high SES groups (Table 4).

Discussion
We found that there was a negative correlation between SES level and risk of post-COVID-19 cardiovascular symptoms, regardless of the COVID-19 severity.Hospitalized patients with low SES were at a higher risk of experiencing post-COVID-19 cardiovascular symptoms.However, non-hospitalized patients with low SES showed a lower risk of post-COVID-19 cardiovascular symptoms.
The results of this study share a number of similarities with previous research.Durstenfeld et al. showed a significant association between low SES and increased post-COVID-19 symptoms in an online cohort study including 13,305 individuals (Durstenfeld et al., 2023).In a cohort study of 16,091 adults, participants with lower education, lower income, and rural residences were more likely to report post-COVID-19 symptoms (Perlis et al., 2022).A retrospective population-based cohort study revealed the odds of experiencing post-COVID symptoms that persist for four or more weeks were 46 % greater in the most socioeconomically disadvantaged group compared to the least disadvantaged group (Shabnam et al., 2023).Furthermore, an analyses of 10 UK longitudinal study revealed a correlation between higher levels of education and a reduced likelihood of experiencing post-COVID-19 symptoms (Thompson et al., 2022).
In this study, we categorized post-COVID-19 symptoms into general, cardiovascular, and respiratory symptoms, and we found the association of SES with only post-COVID-19 cardiovascular symptoms.Several factors are thought to be participated in pathophysiology of long cardiovascular symptoms following SARS-CoV-2 infection including decreased expression of the angiotensin-converting enzyme 2 receptor, hypoxic damage, blood clotting, and systemic inflammation (Parhizgar et al., 2023;Davis et al., 2023).A meta-analysis of 43 studies found that low SES is associated with higher level of systemic inflammatory markers including C-reactive protein and interleukin-6 (Muscatell et al., 2020).In addition, an increasing number of studies have found the higher risk of thrombosis in individual with low SES (Zöller et al., 2012;Isma et al., 2013).Hence, the association of low SES with systemic inflammation and thrombosis may explain the role of SES for predicting post-COVID-19 cardiovascular symptoms.Further studies are required to clarify the mechanisms through which SES is linked with post-COVID-19 cardiovascular symptoms.
Although some studies have investigated the potential risk factors for post-COVID-19 symptoms in non-hospitalized patients (Pływaczewska-Jakubowska et al., 2022;Kisiel et al., 2022), knowledge regarding association of SES with post-COVID-19 symptoms in non-hospitalized patients is still limited.This study suggested the protective role of low SES in predicting post-COVID-19 cardiovascular symptoms in nonhospitalized patients.However, Subramanian et al. found an increased risk of post-COVID-19 symptoms with decreasing SES level in in nonhospitalized adults (Subramanian et al., 2022).These conflicting findings may be attributed to some reasons.Firstly, Subramanian et al. had a large sample size including over 2.4 million participants, leading to the increased statistical power.Secondly, they used indices of multiple deprivation for area deprivation measures of SES, which is a different method that used to measure SES in our study.Besides, while our study found high SES as an associating risk factor of post-COVID-19 cardiovascular symptoms, Subramanian et al. evaluated the association of SES with total post-COVID-19 symptoms.
Further investigations in diverse populations and larger sample sizes are warranted to provide a comprehensive understanding of the role of SES in post-COVID-19 symptomatology among non-hospitalized individuals.This study had some strengths.This study is a longitudinal cohort, which allows for the assessment of long-term effects and outcomes of COVID-19 symptoms.We collected a wide range of data, including SES, demographics, comorbidities, lifestyle factors, and psychological variables.This comprehensive approach allows for a thorough analysis of the association between SES and post-COVID-19 symptoms, while also considering potential confounding factors.We included both hospitalized and non-hospitalized patients with COVID-19, providing a more comprehensive understanding of the impact of SES on post-COVID symptoms.Moreover, this paper included a substantial sample size of 3912 patients, which increases the statistical power and generalizability of the findings.A number of potential limitations need to be considered.First, the symptoms associated with post-COVID are diverse and our study might not have encompassed the complete spectrum of these symptoms.Second, the assessment of SES and other variables relied on   self-reported data, which may introduce reporting bias.
In conclusion, this study found that individuals with lower SES may be at higher risk of developing long-term cardiovascular complications following COVID-19 infection, particularly in hospitalized patients.However, there was no significant correlation between SES and other post-COVID-19 symptoms.These results highlight the importance of considering SES in the evaluation and management of post-COVID-19.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Table 1
Baseline characteristics of patients with COVID 19 based on post-COVID symptoms occurrence among participants of Isfahan COVID Cohort (ICC) study, from 2020 to 2023.

Table 2
Self-reported post-COVID occurrence based on disease severity and socioeconomic status among participants of Isfahan COVID Cohort (ICC) study, from 2020 to 2023.
* Low SES: Less than median socioeconomic score.** High SES: Higher than median socioeconomic score.

Table 3
Hazard ratio and 95% confidence interval of post-COVID symptoms occurrence with socioeconomic status among participants of Isfahan COVID Cohort (ICC) study, from 2020 to 2023.
* Low SES: Less than median socioeconomic score.** High SES: Higher than median socioeconomic score as reference group.

Table 4
Hazard ratio and 95% confidence interval of post-COVID symptoms occurrence with socioeconomic status based on hospitalization among participants of Isfahan COVID Cohort (ICC) study, from 2020 to 2023.
* Low SES: Less than median socioeconomic score.** High SES: Higher than median socioeconomic score as reference group.